tbuckley/cabot-search huggingface dataset:
P006: Clinical outcome of classical Hodgkin Lymphoma patients receiving systemic anti-lymphoma treatment during SARS-COV-2 positivity: Results from the chemo-covid study on behalf of fondazione italiana linfomi
Authors: Chiara Rusconi, Benedetta Puccini, Carlo Visco, Francesca Ricci, Alessandro Re, Vittorio R. Zilioli, Caterina Zerbi, Stefan Hohaus, Federico Mazzon, Manuel Ciceri, Anna Guidetti, Vincenzo Marasco, Luigi Rigacci
Journal: HemaSphere (2022)

Patients (pts) affected by classical Hodgkin Lymphoma (cHL) infected by SARS-CoV-2 are at risk of protracted positivity due to immunodeficiency, and consequent delay of anti-lymphoma treatment may worsen cHL prognosis. Feasibility of chemo-therapy (CT) administration during SARS-CoV-2 infection in cHL pts has not been investigated so far. We collected data of cHL pts enrolled in Haematocovid observational trial and treated with CT while positive for SARS-CoV-2, with the aim to describe CT feasibility and to assess the risk of infection worsening. Thirteen cHL pts treated since May 2020 to May 2022 were included: median age was 39 years (17–68), 6 pts (46%) presented with advanced stage, 8 pts (62%) with B symptoms and 5 pts (38%) with bulky. Seven pts (54%) were treatment-naïve and waiting for ABVD start at time of COVID diagnosis, while in 6 pre-treated pts (46%) SARS-CoV-2 infection occurred after a median time of 18 days (1–42) from administration of the last CT cycle and the median number of prior therapeutic lines was 1 (1–4). Eight pts (62%) previously received m-RNA vaccines, while 5 pts (38%) were infected in the pre-vaccine era. At COVID onset, 6 (46%) pts were asymptomatic and 7 (54%) pauci-symptomatic, being fever (n=5) the most reported symptom; pneumonia was documented in 2 pts, but no case of respiratory failure was described. Viral variant was identified in 7 pts: 1 alpha, 1 delta and 5 omicron, while in 6 pts the presumed variant was derived from pandemic wave (3 pts alpha, 1 pt delta and 3 pts omicron). Four pts (31%) received antiviral treatment, consisting in monoclonal antibodies (n=3) and remdesivir (n=1). A median of 1 cycle of CT (1–2) after a median time of 25 days (1–45) from the first SARS-CoV-2 positivity was delivered. Ten pts (77%) received ABVD, in two cases with bleomycine omission, 1 pt (8%) received escBEACOPP and 2 pts (15%) brentuximab-vedotin. None of the pts experienced COVID worsening following CT administration. Median duration of SARS-CoV-2 positivity was 21 days (9–60). After a median follow-up of 11 months (1–61), one pt died due to cHL progressive disease while positive but asymptomatic for SARS-CoV-2. All the remaining pts were alive and negative for SARS-CoV-2 infection, and 8 pts (62%) achieved cHL complete response. In conclusion, in this preliminary analysis CT administration to high-risk cHL pts positive but asymptomatic for SARS-CoV-2 seems feasible and did not induce clinical worsening of viral infection.
P043: Molecular pathogenesis of Hodgkin lymphoma
Authors: Lilian Beeck, Markus Schneider, Navid Farsijani, Bettina Budeus, Julia Bein, Hendrik Schaefer, Sylvia Hartmann, Martin-Leo Hansmann, Ralf Küppers
Journal: HemaSphere (2022)

Classical Hodgkin lymphoma (cHL) is one of the most frequent lymphomas in the Western world. Its malignant Hodgkin and Reed/Sternberg (HRS) cells are derived from pre-apoptotic germinal center B cells and only account for ca. 1% of the tumor cell mass. The surrounding inflammatory infiltrate is unable to establish an effective immune response against the HRS cells. To better understand HRS cell formation and their molecular pathogenesis, we aim to determine the mutational landscape of HRS cells. HRS cells of a total of 30 cases were isolated by microdissection or flow cytometry and subjected to exome or whole-genome sequencing. We confirmed recurrently mutated genes (e.g. SOCS1, TNFAIP3) but also found novel promising genes such as NLRC5, which is involved in MHCI expression and negative NFkB regulation. Intriguingly, mutational signatures associated with APOBEC and somatic hypermutation were identified. Moreover we are currently analyzing the WGS samples for mutations in gene regulatory regions, miRNA binding sites and gains and losses. Both WGS and WES show a wide variation in their mutational loads.
P019: Unfavorable prognostic value of the predominance of THRLBCL-like histopathological growth patterns in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)
Authors: Elena Dorokhina, T.N. Moiseeva, A.M. Kovrigina, Irirna Shupletsova, L.S. Al-Radi, Yu. A. Chabaeva, Ya.K. Mangasarova
Journal: HemaSphere (2022)

Introduction: NLPHL is characterized by variable morphology and histopathological growth patterns of the tumor substrate. Our study demonstrated the prognostic significance of THRLBCL-like histopathological growth patterns. Purpose: to evaluate the efficacy of 1st line therapy of NLHLP depending on THRLBCL-like histopathological growth patterns in the tumor substrate. Materials and Methods: We analyzed the results of 1st line therapy in 150 patients with NLHLP from 2010 to 2021 yrs. Growth patterns without THRLBCL-like sites were noted in 87/150 (58%), THRLBCL-like patterns - in 63/150 (42%). Additionally, patients with a predominance of THRLBCL-like areas (more than 50% of the cut area) were identified - 32/150 (21%) pts. Results: In 87 (58%) pts with growth patterns without THRLBCL-like areas, 30/87 (34%) pts did not receive chemotherapy; radiation therapy was applied in 20/30 (complete remission (CR) was achieved in all 20 pts); observation after surgical treatment - 10/30 pts; 5 pts - no data. Chemotherapy (R-ABVD - 44%; R-BEACOPP-14–38%; other - 17% pts) was performed in 52/87 (60%) pts; CR was achieved in 68/87 (78%). In 63 (42%) pts with THRLBCL-like patterns, 2/63 (3%) did not receive chemotherapy; 1 patient - in CR after radiation therapy; 1 - under observation after surgical treatment; 4 patients - no data. Chemotherapy (R-ABVD - 18%; R-BEACOPP-14–54%; R-CHOP - 21%; other - 7% pts) received 57/63(90%) pts; CR was achieved in 31/63(49%) pts, partial remission (PR) - in 15/63(24%), stabilization (S) - 2(3%), progression - 4(6%) pts. In 32 (21%) pts with predominance of THRLBCL-like areas, 30 pts underwent chemotherapy (R-ABVD - 16%; R-BEACORP-14–57%; R-CHOP- 27% pts); CR was achieved in 12 (37%), PR-10 (31%), S-1 (3%), progression - 4 (13%) pts. In 2 pts - no data. The 5-year OS for groups with the absence, presence and predominance of THRLBCL-like patterns was 99%, 100%, 68% (p-<0.0001), respectively, the 5-year EFS was 75%, 68%, 32% (p-< 0.0001) respectively. Median follow-up is 34 months. Conclusion: In NLHLP the group of patients with a predominance of THRLBCL-like patterns has the most unfavorable prognosis - CR achieved in 37%, 5-year OS does not exceed 68%, EFS - 32%. Therefore an intensification of first-line therapy is needed for this group of patients.
T083: The Effect of Heart Failure on Management and Outcomes of Older Patients with Hodgkin Lymphoma
Authors: Jenica Upshaw, Jason Nelson, Angie Mae Rodday, Anita Kumar, Andreas Klein, Marvin Konstam, John Wong, Iris Jaffe, Bonnie Ky, Jonathan W. Friedberg, Matthew Mauer, David Kent, Susan K. Parsons
Journal: HemaSphere (2022)

Figure 1: Cumulative incidence of lymphoma mortality (blue), cardiovascular mortality (red) and all-cause mortality (black). Dashed line represents patients with heart failure at the time of lymphoma diagnosis and solid lines patients without heart failure Background: Anthracycline-containing regimens are recommended as first-line treatment for Hodgkin lymphoma (HL); however, the management and outcomes of patients with cardiomyopathy or heart failure (HF) at the time of lymphoma diagnosis is not known. Methods: US Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 1999–2016 were used to identify newly diagnosed HL in patients 66 years and older with one year of Medicare A and B prior to lymphoma diagnosis. Prevalent HF and comorbidities in the year prior to lymphoma diagnosis were identified using International Classification of Diseases codes. Cancer treatment, including doxorubicin and cardioprotective medications (i.e., liposomal doxorubicin and dexrazoxane) were assessed using Healthcare Common Procedure Coding Systems codes. Cause of death was defined using the SEER Cause of Death Recodes. The association between prevalent HF and cancer treatment was estimated using logistic regression with adjustment for comorbidities, social determinants of health and hospital level variables. The association between prevalent HF and cause specific mortality was evaluated using competing risk Cox proportional hazards models with sequential adjustment for comorbidities and cancer treatment. Results: Among 3,348 individuals with newly diagnosed HL, prevalent HF was present in 13.1%. Patients with prevalent HF were less likely to be treated with an anthracycline in the first year after diagnosis (OR 0.42, 95% CI 0.29, 0.60). Among patients with HF who received an anthracycline, dexrazoxane or liposomal doxorubicin was used in only 4.5%. For those with prevalent HF, 1-year lymphoma mortality was 37.4% (95% CI 35.5, 39.5%) [Fig]. In multivariable models adjusting for clinical covariates, prevalent HF was associated with higher lymphoma mortality (HR 1.21, 95% CI 1.03, 1.41); however, the effect of prevalent HF on lymphoma mortality was no longer significant when adding cancer treatment variables to the model (HR 1.05, 95% CI 0.71, 1.56) [Fig]. Prevalent HF was also associated with cardiovascular mortality in fully adjusted models (HR 1.77, 95% CI 1.34, 2.32). Conclusion: HF is common in older patients with HL and is associated with less anthracycline use and higher lymphoma mortality. Dexrazoxane and liposomal doxorubicin are used infrequently. Future randomized trials are needed to determine strategies to decrease lymphoma and cardiac mortality in this high-risk population.
P061: Safety and Dose-Expansion Study of Combination Favezelimab (anti–LAG-3) Plus Pembrolizumab in Anti–PD-1–Naive Patients With Relapsed or Refractory Classical Hodgkin Lymphoma
Authors: Peter Borchmann, Nathalie A. Johnson, David Lavie, Gareth Gregory, Alex F. Herrera, Leonard Minuk, Vladan Vucinic, Philippe Armand, Abraham Avigdor, Robin Gasiorowski, Yair Herishanu, Colm Keane, John Kuruvilla, John Palcza, Pallavi Pillai, Akash Nahar, John Timmerman
Journal: HemaSphere (2022)

Background: PD-1 inhibitors play a key role in the treatment of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), yet novel strategies to enhance responses remain of clinical interest. The multicohort phase 1/2 MK-4280–003 study (NCT03598608) evaluated the safety and efficacy of a LAG-3 inhibitor, favezelimab (MK-4280), + pembrolizumab (pembro) in pts with R/R hematologic malignancies. Cohort 1 focused on anti–PD-1–naive pts with R/R cHL. Methods: Part 1 was the safety lead-in phase to determine the recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible pts in cohort 1 had R/R cHL after autologous stem cell transplantation (ASCT), were ineligible for ASCT, and had no prior anti–PD-1 therapy. Part 1 included pts from all cohorts who received escalating doses (per mTPI design) of pembro IV 200 mg Q3W and favezelimab IV 200 mg or 800 mg Q3W. In part 2, pts received pembro + favezelimab at the established RP2D for ≤35 cycles. The primary end point was safety. ORR was a secondary end point. DOR, PFS, and OS were exploratory end points. Database cutoff was March 21, 2022. Results: Part 1 identified 1 dose-limiting toxicity (DLT; autoimmune hepatitis [grade 4]) among the first 6 pts from all cohorts at the favezelimab 200 mg dose. No DLTs were found after an additional 15 pts at the 800 mg dose; RP2D was defined as 800 mg Q3W + pembro 200 mg Q3W. Of the 30 pts in cohort 1, median age was 40.5 y, 53% had ECOG PS 0, and 80% had ≤3 prior lines of therapy. At database cutoff, 12 of 30 pts had discontinued (4 AEs; 8 PD; 13% due to treatment-related AEs [TRAEs]). No deaths were treatment related. 26 pts (87%) had TRAEs; the most common (≥20%) were hypothyroidism (27%), infusion-related reactions (23%), and fatigue (20%); 7 pts (23%) had grade 3 or 4 TRAEs. After median follow-up of 14.1 mo, ORR was 73% (95% CI, 54–88; CR, 8 [27%]; PR, 14 [47%]). 28 of 29 pts (97%) who received a postdose scan had a baseline reduction in target lesions. Median DOR was not reached (NR; range, 2.6–25.9+ mo); 7 pts (55%) had response ≥12 mo. Median PFS was 19.4 mo (range, 8.5 mo-NR) and median OS was NR (range, NR-NR). Conclusion: Favezelimab 800 mg + pembro 200 mg Q3W demonstrated acceptable safety and effective antitumor activity in anti–PD-1–naive pts with R/R cHL. Comparative studies on its activity to that of single-agent pembro would be of clinical benefit.
P052: Targeting CSN5/JAB1 oncogene in classical Hodgkin Lymphoma (cHL)
Authors: Ioanna Xagoraris, Konstantina Stathopoulou, Stefanie Renken, Andreas Lundqvist, Francois Xavier Claret, Elias Drakos, Georgios Z. Rassidakis
Journal: HemaSphere (2022)

Background: The JAB1 (cJun activation domain binding protein1), initially discovered as a cJun coactivator, represents the fifth component of an evolutionary highly conserved 8 subunit protein complex named COP9 signalosome (CSN5). Accumulating evidence suggests that the CSN5/JAB1 gene operates as an oncogene in cancer through multiple mechanisms including cell cycle control via downregulation of CDK inhibitors. Targeting CSN5/JAB1 activity in cancer is now possible since a novel inhibitor has been developed for clinical use (CSN5i-3, Novartis). The potential role of CSN5/JAB1 in modulation of anti-tumor responses in cHL is unknown to date. Methods: The study group included 118 previously untreated cHL patients with available tissue and clinical data. Expression of CSN5/JAB1 was assessed by immunohistochemistry and a previously validated monoclonal antibody. The in vitro system included 6 cHL cell lines (MDA-V, L1236, L428, L540, KMH2, HDLM2). Expression of proteins were analysed by Western blot and gene expression (mRNA) of type 1 interferons (IFNs), including IFN-β, CXCL10 and IFN-γ, with RT-qPCR. The cHL cell lines were treated with the CSN5i-3 at different concentrations. Silencing of CSN5/JAB1 and NFkB (p65) gene was performed using transient transfection with siRNA constructs. Results: Using a 10% cutoff, CSN5/JAB1 was positive in the neoplastic HRS cells of cHL in 106 of 118 (90%) patients with a predominantly nuclear and weaker cytoplasmic pattern. Treatment of cHL cell lines with increasing concentrations of CSN5i-3 resulted in significant decrease in the cell growth and viability associated with upregulation of the CDK inhibitors p21, p27 and p57. Similarly, CSN5/JAB1 gene silencing resulted in decreased cell growth associated with increased expression of similar cell cycle inhibiting proteins. Inhibition of CSN5/JAB1 activity resulted in significantly increased gene expression of IFN-β, CXCL10 and IFN-γ at a variable degree among the cHL cell lines. Similarly, knocking down CSN5/JAB1 gene led to upregulation of type 1 IFNs. Silencing NFkB gene resulted in decreased levels of CSN5/JAB1 protein suggesting positive regulation of CSN5/JAB1 by NFkB. Conclusion: The CSN5/JAB1 is overexpressed in HRS cells of most cHL patients, promotes cell growth through cell cycle control and downregulates gene expression of type 1 IFNs in vitro. These functions are sufficiently inhibited by the CSN5i-3, designed for clinical use, in preclinical models of cHL.
P005: Age, histotype and stage IV are associated with a shorter survival in patients with Hodgkin lymphoma, even the PET-adapted era. A single center retrospective study.
Authors: Andrea Visentin, Alessandro Cellini, Chiara Adele Cavarretta, Leila Romano Gargarella, Francesco Angotzi, Valeria Ruocco, Simone Zoletto, Stefano Pravato, Marco Pizzi, Federica Vianello, Filippo Crimì, Stefania Vio, Michele Gregianin, Livio Trentin
Journal: HemaSphere (2022)

Figure 1: table 1 and Figure 1 Introduction: Although Hodgkin lymphoma (HL) can be cured in the majority of patients, some patients relapsed, or died due to the disease itself, second malignancies or organ failure caused by previous chemo-radiotherapy. Recently, monoclonal antibodies (mAb) targeting CD30 or PD-1 have been incorporated in the frontline treatment of patients of HL with excellent results. However, it is not clear which patients might benefit more chemo-immunotherapy rather than a traditional chemo-radiotherapy approach Aim: In this study we aimed at identify risk factor associated with shorter survival in patients with classical Hodgkin lymphoma Methods: We collected patients with HL followed at Padova university hospital from 1994 till 2020. Overall survival was calculated as months from diagnosis to death (event) or last known follow-up (censured). Survival curves were compared by the Log-rank test. P values <0.05 were considered as statistically significant Results: Among the 383 classical HL, 313 had enough data and were included in this study. The media age at diagnosis was 37 + 16 years, 27% of patients were older than 45 years, 51% were male, 74% had a nodular sclerosis HL subtype (NSHL), 21% were at stage IV, 32% a bulky disease and 51% denied B symptoms. Ninety-seven % of patients were treated with curative intent with ABVD, ABVD-like or BEACOPP protocols. After a median follow-up of 77 months, 21% of patients relapsed and 9% died. On univariate analysis male gender, age >45 years, not NSHL subtype and stage IV were associated with a shorter OS (Tab 1). However only age >45 years, not NSHL subtype, and stage 4 maintained the independent significance in multivariate analysis (Table 1). Remarkably, a PET-adapted strategy allows to improve the progression free survival of our patients but not the OS. By using the hard ratio half values, we assigned 1 point to male gender and 2 points to age >45 years and stage IV (Tab. 1). Combing these variables, 60% had a 0–1 point (low-risk), 31.5% 2–3 points (int. risk) and 8.5% >=4 points (high-risk). The OS decreased increasing the point scores. The 10-year OS was 94%, 79% and 67% for patients at low, intermediate and high-risk (Fig. 1). Patients at high-risk had almost 10 and 3-fold risk of death than low and intermediate risk patients Conclusions: Despite the optimal outcome of HL with a chemo-radiotherapy approach, novel strategies incorporating anti-CD30 and/or anti-PD-1 mAb are need, in particular for adult stage IV patients.
P080: The BETER-REFLECT Biobank: a REsource For studies on Late Effects of Cancer Treatment
Authors: Adinda Mieras, Annelies Nijdam, Berthe M. P. Aleman, Laurien Daniels, Eva De Jongh, Cécile P.M. Janus, Stijn Krol, Bastiaan D.P. Ta, Francisca Ong, Dick Johan Van Spronsen, Ward Posthuma, Wouter J. Plattel, Rimke Oostvogels, Karijn Verschueren, Josée. M. Zijlstra, Flora E. Van Leeuwen
Journal: HemaSphere (2022)

Due to the introduction of multi-agent chemotherapy and improved radiation techniques, Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) are now malignancies with high cure rates. While the number of long-term lymphoma survivors is increasing, their life expectancy is compromised by late complications of chemotherapy and radiotherapy, which may emerge several decades after initial treatment. Especially second malignancies and cardiovascular diseases cause substantial excess morbidity and mortality. Currently, knowledge about genetic susceptibility and early biomarkers for treatment-related adverse events is scarce, precluding identification of subgroups of patients at higher risk of specific treatment-related adverse events. Such knowledge would allow personalized treatment of future lymphoma patients, ultimately enabling prevention of adverse effects, as well as personalized screening for adverse events in survivors of lymphoma. Knowledge about biomarkers for treatment-related adverse events will benefit the screening program of lymphoma survivors, providing opportunities for earlier diagnosis and treatment of adverse events. Therefore, in the ‘BETER-REFLECT’ project we will establish a national biobank with biospecimens of 5-year lymphoma survivors in order to facilitate research into: - genetic susceptibility for treatment-related adverse events - early biomarkers for adverse events The study population consists of 5-year lymphoma survivors identified through the Dutch BETER project. The nationwide BETER consortium (Better care after (non-)Hodgkin lymphoma, Evaluation of long-term Treatment; Effects and screening Recommendations) aims to reduce the morbidity and mortality from late adverse events of treatment in lymphoma survivors. The consortium has established survivorship care for 5-year HL and DLBCL survivors, who were 15–60 years old at diagnosis. For BETER survivorship care eligible patients in 13 lymphoma treatment centers in the Netherlands are invited to participate in the BETER-REFLECT biobank project (n=3000). From participating survivors we will prospectively collect blood samples. Additionally, Formalin-Fixed Paraffin-Embedded tissue blocks of deceased individuals will be collected (n=1000). Blood samples and tissue blocks are collected to extract germline DNA to investigate genetic susceptibility; serum and plasma is collected to evaluate biomarkers for adverse events. So far, 700 samples have been collected.
T027: High serum levels of Thymus and Activation Related Chemokine (TARC) precede Hodgkin lymphoma diagnosis by several years
Authors: Arjan Diepstra, Ilja M. Nolte, Anke Van Den Berg, Lynn I. Levin, Otoniel Martínez-Maza
Journal: HemaSphere (2022)

Figure 1: Proportion of individuals who can be identified as being affected in the years prior to Hodgkin lymphoma diagnosis. The cut-off is based on the mean + 1.96SD of control samples. NS, nodular sclerosis. Background: Thymus and Activation Related Chemokine (TARC), also known as CCL17, is a chemokine that is highly secreted by tumor cells in classic Hodgkin lymphoma (HL). TARC levels are dramatically increased in serum samples of newly diagnosed HL patients (1). Aim: To evaluate if and how long serum TARC levels are increased prior to a clinical diagnosis of HL. Methods: We measured serum samples from the Department of Defense (DoD) Serum Repository that were collected over several years prior to the diagnosis of HL in the active-duty U.S. military population. Incident HL cases were diagnosed between 1990 and 1999 and included for analysis when a pre-diagnostic serum sample was available (n=101). The median age at diagnosis was 26 years and 10% were female. Pathology review revealed a normal distribution of subtypes and tumor cell EBV status was positive in 23% of cases. For each case, two matched controls were selected from the DoD Serum Repository based on age, sex, race and ethnicity, number of serum samples and sample collection date. The serum samples of these cases and controls were previously analyzed for IL-6, IL-10, soluble CD30 and total IgE (2). TARC levels were measured by a Luminex assay. Differences in log-transformed TARC levels between cases and matched controls were evaluated using mixed model analyses. Results: TARC levels were measured in 211 samples from 101 patients, collected up to 9.8 years before diagnosis, and in 422 samples from matched controls. TARC levels were significantly higher in patients compared to controls (median 921 pg/ml (max. 1.6x105) vs. median 422 pg/ml (max. 3.5x102)), respectively (p=1.2x10-47 in the mixed model analysis). This effect was strongest in nodular sclerosis (NS) and EBV-negative cases, but also present in non-NS and EBV-positive cases. The longest time interval between an increased TARC level and diagnosis was 6.2 years for an individual who developed NS HL, with a logarithmic increase of TARC over time. Conclusions: Increased serum TARC levels often precede diagnosis of classic HL by several years. This implies a long pre-diagnostic phase in which secretion of TARC and the resulting attraction of CD4+ T cells is an important mechanism in pathogenesis. In the clinical setting, serum TARC is being used as a therapy response marker(3) and its indication may be extended to diagnostic and even pre-diagnostic screening. References 1.PMID 22058214; 2. PMID 28341757; 3. PMID 32106342